ORCID Profile
0000-0002-9522-9320
Current Organisation
Olivia Newton-John Cancer Research Institute
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Publisher: Elsevier BV
Date: 10-2020
Publisher: Springer Science and Business Media LLC
Date: 21-07-2016
Abstract: Inflammatory bowel disease (IBD) is an immunoregulatory disorder, associated with a chronic and inappropriate mucosal immune response to commensal bacteria, underlying disease states such as ulcerative colitis (UC) and Crohn’s disease (CD) in humans. Granzyme M (GrzM) is a serine protease expressed by cytotoxic lymphocytes, in particular natural killer (NK) cells. Granzymes are thought to be involved in triggering cell death in eukaryotic target cells however, some evidence supports their role in inflammation. The role of GrzM in the innate immune response to mucosal inflammation has never been examined. Here, we discover that patients with UC, unlike patients with CD, display high levels of GrzM mRNA expression in the inflamed colon. By taking advantage of well-established models of experimental UC, we revealed that GrzM-deficient mice have greater levels of inflammatory indicators during dextran sulfate sodium (DSS)-induced IBD, including increased weight loss, greater colon length reduction and more severe intestinal histopathology. The absence of GrzM expression also had effects on gut permeability, tissue cytokine/chemokine dynamics, and neutrophil infiltration during disease. These findings demonstrate, for the first time, that GrzM has a critical role during early stages of inflammation in UC, and that in its absence colonic inflammation is enhanced.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2014
DOI: 10.1038/NCOMMS5539
Abstract: The cytokine IL-15 is required for natural killer (NK) cell homeostasis however, the intrinsic mechanism governing this requirement remains unexplored. Here we identify the absolute requirement for myeloid cell leukaemia sequence-1 (Mcl1) in the sustained survival of NK cells in vivo. Mcl1 is highly expressed in NK cells and regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3'-UTR of Mcl1. Specific deletion of Mcl1 in NK cells results in the absolute loss of NK cells from all tissues owing to a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane. This NK lymphopenia results in mice succumbing to multiorgan melanoma metastases, being permissive to allogeneic transplantation and being resistant to toxic shock following polymicrobial sepsis challenge. These results clearly demonstrate a non-redundant pathway linking IL-15 to Mcl1 in the maintenance of NK cells and innate immune responses in vivo.
Publisher: The American Association of Immunologists
Date: 15-10-2013
Abstract: Innate lymphocyte populations play a central role in conferring protective immunity at the mucosal frontier. In this study, we demonstrate that T cell factor 1 (TCF-1 encoded by Tcf7), a transcription factor also important for NK and T cell differentiation, is expressed by multiple innate lymphoid cell (ILC) subsets, including GATA3+ nuocytes (ILC2) and NKp46+ ILCs (ILC3), which confer protection against lung and intestinal inflammation. TCF-1 was intrinsically required for the differentiation of both ILC2 and NKp46+ ILC3. Loss of TCF-1 expression impaired the capacity of these ILC subsets to produce IL-5, IL-13, and IL-22 and resulted in crippled responses to intestinal infection with Citrobacter rodentium. Furthermore, a reduction in T-bet expression required for Notch-2–dependent development of NKp46+ ILC3 showed a dose-dependent reduction in TCF-1 expression. Collectively, our findings demonstrate an essential requirement for TCF-1 in ILC2 differentiation and reveal a link among Tcf7, Notch, and Tbx21 in NKp46+ ILC3 development.
Publisher: The American Association of Immunologists
Date: 15-12-2009
Abstract: Tumor progression locus 2 (Tpl2, also known as Map3k8 and Cot) is a serine-threonine kinase critical in innate immunity, linking toll-like receptors (TLRs) to TNF production through its activation of ERK. Tpl2−/− macrophages have abrogated TNF production but overproduce IL-12 in response to TLR ligands. Despite enhanced IL-12 production, Tpl2−/− T cells have impaired IFN-γ production. Therefore, the role of Tpl2 in a bona fide bacterial infection where all of these cytokines are important in host defense is unclear. To address this issue, we infected Tpl2−/− mice with the model pathogen Listeria monocytogenes. We found that Tpl2−/− mice infected i.v. with L. monocytogenes had increased pathogen burdens compared with wild-type mice and rapidly succumbed to infection. Enhanced susceptibility correlated with impaired signaling through TLR2 and nucleotide-binding oligomerization domain 2, two receptors previously shown to mediate Listeria recognition. Surprisingly, TNF production in response to infection was not significantly impaired, even though Tpl2 has been implicated in the regulation of TNF. We found that the role of Tpl2 has cell-type specific effects in regulating TNF and transduces signals from some, but not all, pattern recognition receptors (PRR). In contrast to the cell-type- and receptor-specific regulation of TNF, we found that Tpl2 is essential for IL-1β production from both macrophages and dendritic cells. These studies implicate Tpl2 as an important mediator for collaboration of pattern recognition receptors with danger-associated molecular patterns to induce TNF and IL-1β production and optimal host defense.
Publisher: The American Association of Immunologists
Date: 12-2006
DOI: 10.4049/JIMMUNOL.177.11.7880
Abstract: Although many cytokine receptors generate their signals via the STAT3 pathway, the IL-10R appears unique in promoting a potent anti-inflammatory response (AIR) via STAT3 to antagonize proinflammatory signals that activate the innate immune response. We found that heterologous cytokine receptor systems that activate STAT3 but are naturally refractory (the IL-22R), or engineered to be refractory (the IL-6, leptin, and erythropoietin receptors), to suppressor of cytokine signaling-3-mediated inhibition activate an AIR indistinguishable from IL-10. We conclude that the AIR is a generic cytokine signaling pathway dependent on STAT3 but not unique to the IL-10R.
Publisher: Proceedings of the National Academy of Sciences
Date: 19-10-2004
Abstract: SOCS7 is a member of the suppressor of cytokine signaling (SOCS) family of proteins (SOCS1-SOCS7 and CIS). SOCS proteins are composed of an N-terminal domain of variable length, a central Src homology 2 domain, and a C-terminal SOCS box. Biochemical and genetic studies have revealed that SOCS1, SOCS2, SOCS3, and CIS play an important role in the termination of cytokine and growth factor signaling. However, the biological actions of other SOCS proteins are less well defined. To investigate the physiological role of SOCS7, we have used gene targeting to generate mice that lack expression of the Socs7 gene. Socs7 -/- mice were born in expected numbers, were fertile, and did not exhibit defects in hematopoiesis or circulating glucose or insulin concentrations. However, Socs7 -/- mice were 7-10% smaller than their wild-type littermates, and within 15 weeks of age ≈50% of the Socs7 -/- mice died as a result of hydrocephalus that was characterized by cranial distortion, dilation of the ventricular system, reduced thickness of the cerebral cortex, and disorganization of the subcommissural organ. In situ hybridization studies revealed prominent expression of Socs7 in the brain, suggestive of an important functional role of SOCS7 in this organ.
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.MOLCEL.2006.03.024
Abstract: SOCS3 is essential for regulating the extent, duration, and specificity of cellular responses to cytokines such as G-CSF and IL-6. Here we describe the solution structure of SOCS3, the first structure determined for any SOCS protein, in complex with a phosphotyrosine-containing peptide from the IL-6 receptor signaling subunit gp130. The structure of the complex shows that seven peptide residues form a predominantly hydrophobic binding motif. Regions outside the SOCS3 SH2 domain are important for ligand binding, in particular, a single 15 residue alpha helix immediately N-terminal to the SH2 domain makes direct contacts with the phosphotyrosine binding loop and, in part, determines its geometry. The SH2 domain itself is remarkable in that it contains a 35 residue unstructured PEST motif insertion that is not required for STAT inhibition. The PEST motif increases SOCS3 turnover and affects its degradation pathway, implying that it has an important regulatory role inside the cell.
Publisher: Springer Science and Business Media LLC
Date: 03-2021
DOI: 10.1038/S41590-021-00878-5
Abstract: T cells dynamically interact with multiple, distinct cellular subsets to determine effector and memory differentiation. Here, we developed a platform to quantify cell location in three dimensions to determine the spatial requirements that direct T cell fate. After viral infection, we demonstrated that CD8
Publisher: Frontiers Media SA
Date: 15-01-2019
Publisher: Springer Science and Business Media LLC
Date: 12-09-2010
DOI: 10.1038/NI.1935
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.JAUT.2018.04.003
Abstract: Regulatory T (T
Publisher: EMBO
Date: 02-07-2010
Publisher: Frontiers Media SA
Date: 2013
Publisher: Proceedings of the National Academy of Sciences
Date: 19-09-2006
Abstract: We have generated mice from a N -ethyl- N -nitrosourea mutagenesis screen that carry a mutation in the translation initiation codon of Gata-1 , termed Plt13 , which is equivalent to mutations found in patients with acute megakaryoblastic leukemia and Down syndrome. The Gata-1 locus is present on the X chromosome in humans and in mice. Male mice hemizygous for the mutation ( Gata-1 Plt13 /Y) failed to produce red blood cells and died during embryogenesis at a similar stage to Gata-1 -null animals. Female mice that carry the Plt13 mutation are mosaic because of random inactivation of the X chromosome. Adult Gata-1 Plt13 /+ females were not anemic, but they were thrombocytopenic and accumulated abnormal megakaryocytes without a concomitant increase in megakaryocyte progenitor cells. Gata-1 Plt13 /+ mice contained large numbers of blast-like colony-forming cells, particularly in the fetal liver, but also in adult spleen and bone marrow, from which continuous mast cells lines were readily derived. Although the equivalent mutation to Gata-1 Plt13 in humans results in production of GATA-1s, a short protein isoform initiated from a start codon downstream of the mutated initiation codon, Gata-1s was not detected in Gata-1 Plt13 /+ mice.
Publisher: MDPI AG
Date: 02-2021
Abstract: Chronic inflammation of the gastrointestinal (GI) tract contributes to colorectal cancer (CRC) progression. While the role of adaptive T cells in CRC is now well established, the role of innate immune cells, specifically innate lymphoid cells (ILCs), is not well understood. To define the role of ILCs in CRC we employed complementary heterotopic and chemically-induced CRC mouse models. We discovered that ILCs were abundant in CRC tumours and contributed to anti-tumour immunity. We focused on ILC2 and showed that ILC2-deficient mice developed a higher tumour burden compared with littermate wild-type controls. We generated an ILC2 gene signature and using machine learning models revealed that CRC patients with a high intratumor ILC2 gene signature had a favourable clinical prognosis. Collectively, our results highlight a critical role for ILC2 in CRC, suggesting a potential new avenue to improve clinical outcomes through ILC2-agonist based therapeutic approaches.
Publisher: Elsevier BV
Date: 12-2019
Abstract: T cell factor-1 (TCF-1), encoded by Tcf7, is a transcription factor and histone deacetylase (HDAC) essential for commitment to both the T cell and the innate lymphoid cell (ILC) lineages in mammals. In this review, we discuss the multifunctional role of TCF-1 in establishing these lineages and the requirement for TCF-1 throughout lineage differentiation and maintenance of lineage stability. We highlight recent reports showing promise for TCF-1 as a novel biomarker to identify recently characterized subsets of exhausted CD8
Publisher: Wiley
Date: 25-06-2018
DOI: 10.1111/IMCB.12173
Abstract: Plasmacytoid dendritic cells (pDCs) play a critical role in bridging the innate and adaptive immune systems. pDCs are specialized type I interferon (IFN) producers, which has implicated them as initiators of autoimmune pathogenesis. However, little is known about the downstream effectors of type I IFN signaling that lify autoimmune responses. Here, we have used a chemokine reporter mouse to determine the CXCR3 ligand responses in DCs subsets. Following TLR7 stimulation, conventional type 1 and type 2 DCs (cDC1 and cDC2, respectively) uniformly upregulate CXCL10. By contrast, the proportion of chemokine positive pDCs was significantly less, and stable CXCL10
Publisher: Springer Science and Business Media LLC
Date: 19-01-2015
DOI: 10.1038/NI.3085
Abstract: Foxp3(+) regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.IMMUNI.2015.11.008
Abstract: Tissue-resident memory T (Trm) cells contribute to local immune protection in non-lymphoid tissues such as skin and mucosa, but little is known about their transcriptional regulation. Here we showed that CD8(+)CD103(+) Trm cells, independent of circulating memory T cells, were sufficient for protection against infection and described molecular elements that were crucial for their development in skin and lung. We demonstrated that the T-box transcription factors (TFs) Eomes and T-bet combined to control CD8(+)CD103(+) Trm cell formation, such that their coordinate downregulation was crucial for TGF-β cytokine signaling. TGF-β signaling, in turn, resulted in reciprocal T-box TF downregulation. However, whereas extinguishment of Eomes was necessary for CD8(+)CD103(+) Trm cell development, residual T-bet expression maintained cell surface interleukin-15 (IL-15) receptor β-chain (CD122) expression and thus IL-15 responsiveness. These findings indicate that the T-box TFs control the two cytokines, TGF-β and IL-15, which are pivotal for CD8(+)CD103(+) Trm cell development and survival.
Publisher: Wiley
Date: 09-2012
Abstract: The inflammatory cytokine IL-17 plays a critical role in immunity to infection and is involved in the inflammatory pathology associated with certain autoimmune diseases, such as psoriasis and rheumatoid arthritis. While CD4(+) and CD8(+) T cells are important sources of this cytokine, recent evidence has suggested that γδ T cells and a number of families of innate lymphoid cells (ILCs) can secrete IL-17 and related cytokines. The production of IL-17 by γδ T cells appears to be largely independent of T-cell receptor activation and is promoted through cytokine signalling, in particular by IL-23 in combination with IL-1β or IL-18. Therefore IL-17-secreting γδ T cells can be categorised as a family of cells similar to innate-like lymphoid cells. IL-17-secreting γδ T cells function as a part of mucosal defence against infection, with most studies to date focusing on their response to bacterial pathogens. γδ T cells also play a pathological role in certain autoimmune diseases, where they provide an early source of IL-17 and IL-21, which initiate responses mediated by conventional IL-17-secreting CD4(+) T cells (Th17 cells). ILCs lack an antigen receptor or other lineage markers, and ILC subsets that express the transcriptional factor RORγt have been found to secrete IL-17. Evidence is emerging that these newly recognised sources of IL-17 play both pathological and protective roles in inflammatory diseases as discussed in this article.
Publisher: Elsevier BV
Date: 07-2008
Publisher: American Society of Hematology
Date: 10-2007
DOI: 10.1182/BLOOD-2006-10-055087
Abstract: A pivotal mediator of actin dynamics is the protein cofilin, which promotes filament severing and depolymerization, facilitating the breakdown of existing filaments, and the enhancement of filament growth from newly created barbed ends. It does so in concert with actin interacting protein 1 (Aip1), which serves to accelerate cofilin's activity. While progress has been made in understanding its biochemical functions, the physiologic processes the cofilin/Aip1 complex regulates, particularly in higher organisms, are yet to be determined. We have generated an allelic series for WD40 repeat protein 1 (Wdr1), the mammalian homolog of Aip1, and report that reductions in Wdr1 function produce a dramatic phenotype gradient. While severe loss of function at the Wdr1 locus causes embryonic lethality, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles. Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding. Autoinflammatory disease, which is bone marrow–derived yet nonlymphoid in origin, is characterized by a massive infiltration of neutrophils into inflammatory lesions. Cytoskeletal responses are impaired in Wdr1 mutant neutrophils. These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types.
Publisher: Rockefeller University Press
Date: 29-05-2015
DOI: 10.1084/JEM.20181778
Abstract: Interleukin (IL)-17–producing CD8+ T (Tc17) cells have emerged as key players in host-microbiota interactions, infection, and cancer. The factors that drive their development, in contrast to interferon (IFN)-γ–producing effector CD8+ T cells, are not clear. Here we demonstrate that the transcription factor TCF-1 (Tcf7) regulates CD8+ T cell fate decisions in double-positive (DP) thymocytes through the sequential suppression of MAF and RORγt, in parallel with TCF-1–driven modulation of chromatin state. Ablation of TCF-1 resulted in enhanced Tc17 cell development and exposed a gene set signature to drive tissue repair and lipid metabolism, which was distinct from other CD8+ T cell subsets. IL-17–producing CD8+ T cells isolated from healthy humans were also distinct from CD8+IL-17− T cells and enriched in pathways driven by MAF and RORγt. Overall, our study reveals how TCF-1 exerts central control of T cell differentiation in the thymus by normally repressing Tc17 differentiation and promoting an effector fate outcome.
Publisher: Elsevier BV
Date: 04-2006
Publisher: Elsevier BV
Date: 06-2015
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1038/MI.2014.93
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.CYTO.2014.06.002
Abstract: The body's surface provides a critical barrier shielding us from various mechanical and pathogenic insults by virtue of the physical protection it provides and the presence of specialized populations of innate lymphoid cells (ILCs) that sense inflammatory signals induced by pathogens. This response plays a central role in the development and activation of early immune responses. While ILCs depend on common γ-chain cytokine signaling for their development, an essential component of the armory of these cells is their capacity to produce defensive cytokines when activated by viruses, microbes and other parasites. In this review, we describe the multiple intrinsic and extrinsic pathways that comprise the cytokine circuitry regulating the development and function of ILC necessary for protective immunity.
Publisher: Springer Science and Business Media LLC
Date: 03-03-2013
DOI: 10.1038/NI.2545
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.IMMUNI.2018.03.003
Abstract: Polymorphisms in NFKB1 that diminish its expression have been linked to human inflammatory diseases and increased risk for epithelial cancers. The underlying mechanisms are unknown, and the link is perplexing given that NF-κB signaling reportedly typically exerts pro-tumorigenic activity. Here we have shown that NF-κB1 deficiency, even loss of a single allele, resulted in spontaneous invasive gastric cancer (GC) in mice that mirrored the histopathological progression of human intestinal-type gastric adenocarcinoma. Bone marrow chimeras revealed that NF-κB1 exerted tumor suppressive functions in both epithelial and hematopoietic cells. RNA-seq analysis showed that NF-κB1 deficiency resulted in aberrant JAK-STAT signaling, which dysregulated expression of effectors of inflammation, antigen presentation, and immune checkpoints. Concomitant loss of STAT1 prevented these immune abnormalities and GC development. These findings provide mechanistic insight into how polymorphisms that attenuate NFKB1 expression predispose humans to epithelial cancers, highlighting the pro-tumorigenic activity of STAT1 and identifying targetable vulnerabilities in GC.
Publisher: Rockefeller University Press
Date: 20-05-2013
DOI: 10.1084/JEM.20121588
Abstract: Retinoic acid (RA), a vitamin A metabolite, modulates mucosal T helper cell responses. Here we examined the role of RA in regulating IL-22 production by γδ T cells and innate lymphoid cells in intestinal inflammation. RA significantly enhanced IL-22 production by γδ T cells stimulated in vitro with IL-1β or IL-18 and IL-23. In vivo RA attenuated colon inflammation induced by dextran sodium sulfate treatment or Citrobacter rodentium infection. This was associated with a significant increase in IL-22 secretion by γδ T cells and innate lymphoid cells. In addition, RA treatment enhanced production of the IL-22–responsive antimicrobial peptides Reg3β and Reg3γ in the colon. The attenuating effects of RA on colitis were reversed by treatment with an anti–IL-22 neutralizing antibody, demonstrating that RA mediates protection by enhancing IL-22 production. To define the molecular events involved, we used chromatin immunoprecipitation assays and found that RA promoted binding of RA receptor to the IL-22 promoter in γδ T cells. Our findings provide novel insights into the molecular events controlling IL-22 transcription and suggest that one key outcome of RA signaling may be to shape early intestinal immune responses by promoting IL-22 synthesis by γδ T cells and innate lymphoid cells.
Publisher: The American Association of Immunologists
Date: 14-12-2009
Abstract: The protein kinase encoded by the Tpl2 proto-oncogene regulates ERK activation and cytokine gene expression in macrophages in response to LPS and TNF-α. In this study we show that OVA-immunized Tpl2−/− mice express high levels of IgE and develop more severe bronchoalveolar eosinophilic inflammation than Tpl2+/+ controls, when challenged with OVA intranasally. Bronchoalveolar exudates and supernatants of OVA-stimulated splenocytes from immunized Tpl2−/− mice express elevated levels of IL-4 and IL-5, suggesting that Tpl2 ablation promotes the Th2 polarization of the T cell response. Anti-CD3 stimulation of CD4+ T cells of wild-type and Tpl2 knockout mice revealed that Tpl2 ablation gives rise to a cell autonomous T cell defect that is primarily responsible for the Th2 polarization of the T cell response to Ag. This observation was further supported by experiments addressing the expression of Th1 and Th2 cytokines in OVA-stimulated mixed cultures of CD4+ T cells from Tpl2+/+/OT2 or Tpl2−/−/OT2 mice and dendritic cells from Tpl2+/+ or Tpl2−/− mice. Further studies revealed that Th1 cells express significantly higher levels of Tpl2 than Th2 cells. As a result, Tpl2−/− Th1 cells exhibit a stronger defect in ERK activation by anti-CD3 than Th2 cells and express low levels of T-bet. Given that the development of Th1 and Th2 cells depends on positive feedback signals from the T cells, themselves, the functional defect of the Tpl2−/− Th1 cells provides a mechanistic explanation for the T cell autonomous Th2 polarization in Tpl2−/− mice.
Publisher: Rockefeller University Press
Date: 10-11-2008
DOI: 10.1084/JEM.20081461
Abstract: Tpl2 (Tumor progression locus 2), also known as Cot/MAP3K8, is a hematopoietically expressed serine-threonine kinase. Tpl2 is known to have critical functions in innate immunity in regulating tumor necrosis factor–α, Toll-like receptor, and G protein–coupled receptor signaling however, our understanding of its physiological role in T cells is limited. We investigated the potential roles of Tpl2 in T cells and found that it was induced by interleukin-12 in human and mouse T cells in a Stat4-dependent manner. Deficiency of Tpl2 was associated with impaired interferon (IFN)-γ production. Accordingly, Tpl2−/− mice had impaired host defense against Toxoplasma gondii with reduced parasite clearance and decreased IFN-γ production. Furthermore, reconstitution of Rag2−/− mice with Tpl2-deficient T cells followed by T. gondii infection recapitulated the IFN-γ defect seen in the Tpl2-deficient mice, confirming a T cell–intrinsic defect. CD4+ T cells isolated from Tpl2−/− mice showed poor induction of T-bet and failure to up-regulate Stat4 protein, which is associated with impaired TCR-dependent extracellular signal-regulated kinase activation. These data underscore the role of Tpl2 as a regulator of T helper cell lineage decisions and demonstrate that Tpl2 has an important functional role in the regulation of Th1 responses.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.IMMUNI.2015.12.007
Abstract: The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id2. These results shift the current paradigm on the role of ID2, indicating that it is required not only to antagonize E-proteins during NK cell commitment, but constantly required to titrate E-protein activity to regulate NK cell fitness and responsiveness to IL-15.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-10-2023
Publisher: Rockefeller University Press
Date: 04-08-2014
DOI: 10.1084/JEM.20140145
Abstract: Innate lymphoid cell (ILC) populations protect against infection and are essential for lymphoid tissue formation and tissue remodeling after damage. Nfil3 is implicated in the function of adaptive immune lineages and NK cell development, but it is not yet known if Nfil3 regulates other innate lymphoid lineages. Here, we identify that Nfil3 is essential for the development of Peyer’s patches and ILC2 and ILC3 subsets. Loss of Nfil3 selectively reduced Peyer’s patch formation and was accompanied by impaired recruitment and distribution of lymphocytes within the patches. ILC subsets exhibited high Nfil3 expression and genetic deletion of Nfil3 severely compromised the development of all subsets. Subsequently, Nfil3−/− mice were highly susceptible to disease when challenged with inflammatory or infectious agents. Thus, we demonstrate that Nfil3 is a key regulator of the development of ILC subsets essential for immune protection in the lung and gut.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2018
DOI: 10.1038/S41467-018-06125-0
Abstract: Anti-microbial signaling pathways are normally triggered by innate immune receptors when detecting pathogenic microbes to provide protective immunity. Here we show that the inflammasome sensor Nlrp1 aggravates DSS-induced experimental mouse colitis by limiting beneficial, butyrate-producing Clostridiales in the gut. The colitis-protective effects of Nlrp1 deficiency are thus reversed by vancomycin treatment, but recapitulated with butyrate supplementation in wild-type mice. Moreover, an activating mutation in Nlrp1a increases IL-18 and IFNγ production, and decreases colonic butyrate to exacerbate colitis. We also show that, in patients with ulcerative colitis, increased NLRP1 in inflamed regions of the colon is associated with increased IFN-γ . In this context, NLRP1 , IL-18 or IFN-γ expression negatively correlates with the abundance of Clostridiales in human rectal mucosal biopsies. Our data identify the NLRP1 inflammasome to be a key negative regulator of protective, butyrate-producing commensals, which therefore promotes inflammatory bowel disease.
Publisher: Elsevier BV
Date: 09-2012
Publisher: Springer Science and Business Media LLC
Date: 30-11-2015
DOI: 10.1038/NI.3332
Publisher: Elsevier BV
Date: 12-2021
Location: Australia
No related grants have been discovered for Lisa Mielke.